Another coup for targeted therapy

Julia Draznin Maltzman, MD The Abramson Cancer Center of the University of Pennsylvania

The news

Genentech won US FDA approval on Thursday (2/24/04) for its greatly anticipated new drug, Bevacizumab (Avastin). Bevacizumab is approved for use in previously untreated metastatic colorectal cancer.

The data

Approval is based on the data from a phase III study presented at ASCO 2003. The study included just less than 1,000 patients with metastatic colon cancer randomized into three arms. These include: (1) 5-Fluorouracil (5-FU), Leucovorin (LV), and Irinotecan, (the combination of these three chemotherapeutics is also known as the IFL or the Saltz regimen), (2) IFL with Bevacizumab and (3) 5-FU/LV and Bevacizumab alone. The results confirmed that patient survival increased by 30 percent, from 15.6 months to 20.3 months by the addition of Bevacizumab to the IFL regimen. Progression free survival was 6.2 months in the IFL group that did not receive Bevacizumab and 10.6 months in the group that did. This represents the largest improvement in survival time reported in a clinical study attributable to the addition of a single targeted agent to conventional chemotherapy.

Side effects

Bevacizumab was very well tolerated. The only adverse event seen with significantly greater frequency in the Bevacizumab arm is elevation in blood pressure. There were no reports of grade 4 hypertension but a 10.9% incidence of grade 3 hypertension was seen. There were slightly higher incidences of proteinuria and thrombo-embolic events in the Bevacizumab treated groups.

How does Bevacizumab work?

Bevacizumab is known as an anti-angiogenesis agent that blocks the tumor cells Vascular Endothelial Growth Factor (VEGF) Receptor. Bevacizumab is a humanized monoclonal antibody that binds directly to VEGF and prevents it from interacting with its receptor on the endothelial cell. By blocking the interaction between the receptor and its complementary protein, Bevacizumab interferes with any signals the protein may convey to the cell, such as signals to grow, divide, and invade.

What is VEGF?

Blood vessels are lined with cells called endothelial cells. For the most part these cells serve maintain the integrity of the blood vessels. However, various hormones and proteins can direct these cells. Cancer cells, for example, secrete proteins that command endothelial cells to grow and extend into the tumor mass itself. Once blood supply is established, the cancer can grow and thrive. One such protein is called Vascular Endothelial Growth Factor (VEGF). VEGF is secreted by the tumor and acts on the VEGF receptors found on the endothelial cells. Once the VEGF protein binds to its complementary receptor on the endothelial cell, a number of signals or messages are initiated within the cell. These signals include cell activation and proliferation, cell survival and an increase in endothelial cell migration. Researchers who study angiogenesis investigate both the proteins secreted by tumors and the cells that they command. Researchers hope that by affecting the tumor's blood supply, the cancer growth may be stopped and the tumor may be eradicated.

What is happening in the tumor?

As the tumor grows and recruits more and more blood supply, these small capillaries become very disorganized. There is lack of direction to the flow of blood and empty vessels may form. The chaotic vascular system that forms eventually results in increased pressure. As the pressure builds these vessels become leaky. To use an analogy, when more and more pressure builds with in a pipe due to increased or turbulent water flow, week joints in the pipes may begin to leak out water. Similarly, as pressure increases within the blood vessels, smaller proteins and plasma can ooze out. These proteins will have nowhere to go and will squeeze their way in between the tumor cells themselves. The build up of proteins and plasma in the tumor mass itself is called edema. As the edema builds, tumor cells will become more starved for oxygen and other nutrients. Lack of oxygen, in turn, causes the cancer cells to secrete even more VEGF and propagate this viscous cycle.

Beyond the colon

Beyond current approval, Genentech is looking to investigate Bevacizumab's application for use in breast, kidney, and lung cancers. Similarly, studies are on the way to examine the antibody's action in earlier stage colon caner and with other chemotherapy combinations. Other studies in pancreatic, ovarian, prostate and hematologic cancers are already on their way.

The down side

Bevacizumab will cost about $46,600 per patient for a typical treatment cycle of about eleven months. Gaining approval by the FDA will likely mean that it will be covered by insurance carriers; however, the true consequences remain to be seen.